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This article was downloaded by: [Abdel-Wahab, B. F.]On: 12 August 2010Access details: Access Details: [subscription number 925755755]Publisher Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
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2-Amino-4-thiazolidinones: synthesis and reactionsM. A. Metwallya; Abdelbasset A. Farahatbc; Bakr F. Abdel-Wahabd
a Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt b Departmentof Chemistry, Georgia State University, Atlanta, GA, USA c Department of Pharmaceutical OrganicChemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt d Department of Chemistry,Faculty of Science & Arts, King Abdulaziz University, Khulais, Saudi Arabia
Online publication date: 12 August 2010
To cite this Article Metwally, M. A. , Farahat, Abdelbasset A. and Abdel-Wahab, Bakr F.(2010) '2-Amino-4-thiazolidinones: synthesis and reactions', Journal of Sulfur Chemistry, 31: 4, 315 — 349To link to this Article: DOI: 10.1080/17415993.2010.482155URL: http://dx.doi.org/10.1080/17415993.2010.482155
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Journal of Sulfur ChemistryVol. 31, No. 4, August 2010, 315–349
REVIEW ARTICLE
2-Amino-4-thiazolidinones: synthesis and reactions
M.A. Metwallya*, Abdelbasset A. Farahatb,c and Bakr F. Abdel-Wahabd
aDepartment of Chemistry, Faculty of Science, Mansoura University, P.O. Box 23, Mansoura, Egypt;bDepartment of Chemistry, Georgia State University, Atlanta, GA 30303, USA; cDepartment of Pharmaceu-tical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; dDepartmentof Chemistry, Faculty of Science & Arts, King Abdulaziz University, Khulais, Saudi Arabia
(Received 9 January 2010; final version received 28 March 2010 )
Methods for the synthesis of 2-amino-4-thiazolidinones and their chemical properties are reviewed forthe first time. 2-Amino-4-thiazolidinones are synthetically versatile substrates, as they can be used for thesynthesis of a large variety of biologically active compounds, such as thiazolodihydropyrazoles, thiazolo-triazines, and thiazolotetrahydropyrimidones, and as a raw material for drug synthesis. The high reactivityof amino and active methylene groups next to the carbonyl of the thiazolidin ring represents useful targetsfor many organic reactions.
Keywords: thiazolidine; 5-ones; synthesis; reactions; applications
1. Introduction
Amino-4-thiazolidinones, or their tautomeric forms, named pseudothiohydantoin have encoun-tered a prominent place in heterocyclic chemistry, due to the high practical value of these com-pounds, and the broad spectrum of their biological activities. For example, 2,4-dioxothiazolidinederivatives are useful as hypoglycemics and hypolipidemic agents (1), and as intermediates inthe synthesis of antidiabetic drugs (2). Other compounds derived from 2-amino-4-thiazolidinonesare used as anticancer agents (3, 4), antiproliferative (5), antiinflammatory (6), cardiotonic (7),tuberculostatic (8, 9) and as dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflam-matory activity (10). Despite this versatile importance, 2-amino-4-thiazolidinones have not beenpreviously reviewed. The main purpose of this review is to present a survey of the chemistry of2-amino-4-thiazolidinones and provide useful and up-to-date data for medicinal chemists.
2. Synthesis of 2-amino-4-thiazolidinones
2.1. From α-halo carboxylic acid derivatives
2-Imino-4-thiazolidone HCl 1 was synthesized from ethyl chloroacetate and thiourea in 95%ethanol, neutralization in sodium acetate solution under reflux gave 2-imino-4-thiazolidone 2
*Corresponding author. Email: [email protected]
ISSN 1741-5993 print/ISSN 1741-6000 online© 2010 Taylor & FrancisDOI: 10.1080/17415993.2010.482155http://www.informaworld.com
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(Scheme 1) (11–15).
H2N NH2
S
+ Cl CO2Et
95%EtOH
92%
N
S NH2
OHCl AcONa, water
84%
N
S NH2
O
1 2
NH
S NH
O
2
Scheme 1. Synthesis of 2-imino-4-thiazolidone.
5-Phenyl-2-amino-4-thiazolinone 3 has been synthesized from ethyl 2-chloro-2-phenylacetate,thiourea, and anhydrous sodium acetate in ethanol (Scheme 2) (16).
CO2EtPh
Cl
H2N
S
NH2
anhd. AcONa
EtOH S
N O
H2N
Ph3
Scheme 2. Route to 5-Phenyl-2-amino-4-thiazolinone.
Treatment of 2-chloroesters 4 with thiourea afforded 2-aminothiazolidin-4-ones 5 (Scheme 3)(17, 18).
Ar
Cl
CO2Methiourea
55–65%
N
S
O
H2NAr
Ar=[2,4-(OEt)2; 3,4-Me2; 4-Cl-3-MeO; 3,5-(MeO)2; 4-NHCOMe,3-MeO]phenyl
4 5
Scheme 3. Synthesis of 2-aminothiazolidin-4-ones.
Oxiranyl- and thiiranyl-substituted 2-imino-thiazolidine-4-ones 7 (Scheme 4) were preparedby refluxing thiourea with ethyl 2-chloro-3-(oxiran-2-yl)propanoate (6, X=O) or ethyl 2-chloro-3-(thiiran-2-yl)propanoate (6, X=S) (19).
HN
S
O
HN
XO
X
EtO
Cl
S
NH2H2N +
6 7
X = O, S
Scheme 4. Synthesis of substituted 2-imino-thiazolidine-4-ones.
2-[(2-Amino-4,5-dihydro-4-oxothiazol-5-yl)methyl]isothiourea 9 was obtained upon treatmentof methyl 2,3-dibromopropanoate 8 with thiourea (Scheme 5) (19).
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OMeO
BrBr
thiourea
75%
N
SH2N
O
S
NH
NH2x 2HBr
98
Scheme 5. Synthesis of isothiourea.
Long-chain-substituted 2-imino-4-thiazolidinones and 2,4-thiazolidinediones 11 were pre-pared in about 80% yield by condensation of α-bromo-carboxylic acids 10 with thiourea(Scheme 6) (20).
Br
HO2C (CH2)n
Me thioureaNHS
O
NH
n(H2C)
Me
1011
n = 13, 15, 19
Scheme 6. Synthesis of 2-imino(oxa)-4-thiazolidinones.
Reaction of 2-bromo-3-aminopropionic acid 12 with thiourea in AcOH gave 53% thioureaderivative 13, which upon treatment with HBr gave 76% thiazoline derivative 14 (Scheme 7) (21).
OHO
NH2.HBrBr thiourea/AcOH
53%
OOH
.H2N SNH
NH2
HBr N
SH2N
O
NH2
76%
.2HBr
12 4131HBr
Scheme 7. Synthesis of thiazoline derivative.
5,5-Dialkyl-2-imino-4-thiazolidones 16 were prepared by condensing thiourea with dialkyl-substituted bromoacetic acids or the acid chlorides 15 (Scheme 8) (22).
X = OH, Cl; R1/R2 = Et/Et, Et/Pr, Et/iso-Bu, Et/sec-Bu, ethyl/1-methylbutyl
thiourea, AcONa, EtOH
N
SH2N
O
R1R2
6151
R2R1Br
H3CO
X CH3
Scheme 8. Synthesis of 5,5-dialkyl-2-imino-4-thiazolidones.
5,5-Disubstituted-2-imino-4-thiazolidones 18 were prepared by refluxing of α-bromoacidchlorides 17 with thiourea in glacial acetic acid (Scheme 9) (23).
OClEt
R Br
R = Et, Bu
thiourea, AcOH
77–84%
N
SH2N
O
R
Et
1718
Scheme 9. Synthesis of 5,5-disubstituted-2-imino-4-thiazolidones.
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318 M.A. Metwally et al.
Reaction of α-bromo acetyl bromide and thiourea afforded 2-amino-4-thiazolidinone 2 in 25%yield (Scheme 10) (24).
S
NH2H2N+
O
BrBr
80 °C, 3 h
25%
N
S NH2
O
2
Scheme 10. Route to 2-amino-4-thiazolidinone 2.
Refluxing ethyl 6-(benzamido)-2-bromohexanoate 19 with thiourea in ethanol gave theiminothiazolidinone 20 (Scheme 11) (25).
O
EtO
HN
O
Ph
Br
S
H2N NH2+
EtOH, reflux, 20 min
69% NH
O
Ph
HN
S
O
HN
19 20
Scheme 11. Synthesis of iminothiazolidinone.
The synthesis of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones 22, which have hypo-glycemic and hypolipidemic activities, was described. Thus treatment of α-bromoesters21 with thiourea in the presence of sodium acetate afforded 2-amino-4-thiazolidinones 22(Scheme 12) (26).
Br
MeO2C
O
R2
N
R
R1
S
NH2H2N
AcONa O
R2
N
R
R1NS
O
H2N
21 22
Scheme 12. Synthesis of 2-amino-4-thiazolidinones.
α-Bromoester 23 underwent cyclocondensation with thiourea to give the imino compound 24(Scheme 13) (27).
N
Et
OBr
MeO2Cthiourea
N
Et
OS
N
O
H2N23 24
Scheme 13. Synthesis of imino compound.
Ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]propionate 25 was condensed withthiourea followed by hydrolysis using HCl to give 5-[4-(2-methyl-2-phenylpropoxy)benzyl]thiazolidine-2,4-dione 27 which possess hypoglycemic and hypolipidemic activities(Scheme 14) (28).
OEtOOMe
Ph
Me
Cl
thiourea OOMe
Ph
Me
S
N
NH2
H2O/HCl
sulfolane
OOMe
Ph
Me
S
NH
O
25 26 27
Scheme 14. Synthesis of (AL-321).
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Reaction of α-haloester 28 with thiourea in the presence of sulfolane afforded 2-((4-((2-amino-4-oxo-4,5-dihydrothiazol-5-yl)methyl)phenoxy)methyl)-2,5,7,8-tetramethylchroman-6-ylacetate 29 and 2-((4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)methyl)-2,5,7,8-tetramethyl-chroman-6-yl acetate 30 in 26% and 39% yields, respectively (Scheme 15) (29).
O
MeO
MeMe
Me
AcO
Cl
CO2Etthiourea,sulfolane O
Me
O
MeMe
Me
AcON
S NH2
O
26%
O
MeO
MeMe
Me
AcONH
S O
O
39%
2829
30
Scheme 15. Synthesis of tetramethylchroman-6-yl acetates.
2-Phenylbenzo[d]oxazol-5-amine 31 was converted to 2-amino-5-((2-phenylbenzo[d]oxazol-5-yl)methyl)thiazol-4(5H)-one 32, upon treatment with methyl acrylate followed by reaction withthiourea (Scheme 16) (30).
O
NPh
H2N1. methyl acrylate, HCl,CuO, Me2CO
2. thiourea, NaOAc
O
NPh
S
NO
NH2
31 32
Scheme 16. Synthesis of thiazol-4(5H )-one.
1-Carbaniloyl-2-oxo-3-pyrrolidinecarboxylates 33 were brominated to give 34. These under-went substitution and cyclization reactions with thiourea to give spiro[pyrrolidinethiazolidine] 35in 29–40% yields (Scheme 17) (31).
N
O
CO2EtO
NHR
Br2/CCl2 N
O
CO2EtO
NHR
Brthiourea/EtOH
29–40%
S
N
H2N
O
N
O O
NH
R
33 5343
Scheme 17. Synthesis of spiro[pyrrolidinethiazolidine].
Methyl 3-(7-(benzyloxy)quinolin-3-yl)-2-bromopropanoate 36 was cyclocondensed withthiourea in the presence of AcONa in ethanol under reflux for 7 h to give 86% 2-imino-5-[(7-benzyloxy-3-quinolyl)methyl]thiazolidin-4-one 37 which has an antihyperglycemic effect(Scheme 18) (32).
O
O
BrN
OPh
Me +
S
H2N NH2
EtOH, reflux, 7 h
86%
S N
ON
OPh
H2N
36 37
Scheme 18. Synthesis of thiazolidin-4-one.
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2-Aminothiazol-4(5H)-one 39 was prepared in 82% by reaction of α-chloro-ester 38 withthiourea in ethanol in the presence of sodium acetate (Scheme 19) (33).
NS
O
H2N
H2C
ON
Me
NCl
O
ON
Me
N
EtO
S
H2N NH2
AcONa/EtOH82%38 39
Scheme 19. Synthesis of 2-aminothiazol-4(5H )-one.
Thiazolidin-4-one 41 of hypoglycemic and hypolipidemic properties was prepared bytreatment of ethyl 2-chloro-3-(4-(2-phenylpropan-2-yloxy)phenyl)propanoate 40 with thiourea(Scheme 20) (34).
OPh
MeMeCl
CO2Et
thiourea
O
Ph
Me
MeS
N
O
H2N40 41
Scheme 20. Synthesis of thiazolidin-4-one.
Reaction between 2,9,10-tribromostearic acid 42 and thiourea afforded amino thiazolidinone43 (Scheme 21) (35).
(CH2)7
CH3O
HO
Br
Br
Br
thiourea (H2C)7CH3
O
Br Br
S
N NH2
42 43
Scheme 21. Synthesis of aminothiazolidinone.
Reaction of ethyl 4-bromo-5-oxo-3-phenyl-4,5-dihydroisoxazole-4-carboxylate 44 withthiourea afforded 2-amino-9-phenyl-7-oxa-1-thia-3,8-diazaspiro[4.4]nona-2,8-diene-4,6-dione45 (Scheme 22) (36).
NO
Ph
O
EtO2C Br
+
S
H2N NH2
KF/DMF
H2O71%
N
OS
N
O
NH2
Ph
O44 45
Scheme 22. Synthesis of 3,8-diazaspiro[4.4]nona-2,8-diene-4,6-dione.
α-Bromocarbonyl compound 46 reacted with thiourea to give thiazole derivative 47(Scheme 23) (37).
MeO2CCO2Me
Br
thiourea N
SH2N
O
CO2Me46 47
Scheme 23. Synthesis of thiazole derivative.
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2-Alkyl/arylimino-5-carbethoxythiazolidin-4-ones 49 have been synthesized by the interactionof thiocarbamides 48 with diethyl bromomalonate (Scheme 24) (38).
CO2Et
CO2EtBr+
S
NH2NH
R
HN
S
O
CO2Et
N
R
NH4OH / H2O
R = H, Me, Ph, 4-MeC6H4, 4-ClC6H4, 2-MeOC6H4
48 49
Scheme 24. Synthesis of 2-subs.imino-5-carbethoxythiazolidin-4-ones.
Condensation of diethyl 2-chloro-2-arylmethylmalonates 50 with thiourea afforded 2-aminothiazolidin-4-one derivatives 51 (Scheme 25) (17).
Ar O
O OEtOEt
Clthiourea N
SH2N
O
Ar20–30%
Ar = [2,4-diethoxy; 3,4-dimethoxy; 3-ethoxy,4-hydroxy; 3-chloro,4-hydroxy,5-methoxy]phenyl
50 51
Scheme 25. Synthesis of 2-aminothiazolidin-4-one derivatives.
Phthalic anhydride was allowed to react with 3-aminopropanoic acid to give 3-(1,3-dioxoisoindolin-2-yl)propanoic acid 52, which upon bromination followed by reaction withthiourea afforded 2-[(2-amino-4-oxo-4,5-dihydrothiazol-5-yl)methyl]isoindoline-1,3-dione 53.Hydrolysis of 53 in the presence of hydrobromic acid gave 2-amino-5-(aminomethyl)thiazol-4(5H)-one 54 (Scheme 26) (21).
O
O
O
+ H2N CO2H N
O
O
CO2H1.P, Br22.HBr/H2O
3. thiourea, AcOHN
O
O
NS
O
NH2
HBr, H2O, BuOH
C6H676%
H2N NS
O
NH2
5253
54
Scheme 26. Synthesis of 2-amino-5-(aminomethyl)thiazol-4(5H )-one.
Substituted S-(1-phenylpyrrolidin-2-on-3-yl)isothiuronium salts 56 in weakly basic mediaunderwent intramolecular recyclization reaction in which the γ -lactam cycle is split and athiazolidine cycle 57 is formed (Scheme 27) (39–41).
N
OR1
Br +
S
R3HN NHR2N
OR1
S NR2
NHR3
x HBr
weak base
HN
R1S
N
O
R2
NR3
R1 = NO2, MeO; R2, R3 = H, Me
5556
57
Scheme 27. Synthesis of thiazolidine.
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2.2. From chloroacetamides
Method for the removal of chloroacetyl groups is used for the preparation of 2-imino-4-thiazolidinone. Thus, 1-adamantyl methyl amine 58 was acylated with chloroacetyl chloride togive the corresponding amide 59, which was then treated with thiourea to give 2-aminothiazol-4(5H)-one 2 in addition to the recovering of the starting material as a by-product (Scheme 28) (42).
H2N ClCH2COCl NH
O
Clthiourea
58%
N
S NH2
O
58 59 2
+
H2N
Scheme 28. Pathway to 2-aminothiazol-4(5H )-one.
2-(2-(2-Chloroacetamido)acetamido)acetic acid 60 was treated with thiourea to give a mix-ture of 2-(2-aminoacetamido)acetic acid 61 and 2-aminothiazol-4(5H)-one 2. While 4-(2-chloroacetyl)piperazine-1-carbaldehyde 62 gave a mixture of piperazine-1-carbaldehyde 63 and2-aminothiazol-4(5H)-one 2 (Scheme 29) (43).
O
Cl
NH
O
HN CO2H thiourea
EtOHH2N
O
HN CO2H +
N
S NH2
O
N
N
O
Cl
CHO
thiourea
EtOH, water
N
S NH2
ON
NH
CHO
+
2
2
60 61
62 63
Scheme 29. Synthesis of 2-aminothiazol-4(5H )-one.
Condensation of 2-chloro-N ,N -dipropylacetamide 64 with thiourea in ethanol gave 2-amino-4-thiazolidinone 2 as a side product (Scheme 30) (44, 45).
O
ClN
thiourea/EtOHNH +
86%64
N
S NH2
O
2
Scheme 30. Synthesis of amino-4-thiazolidinone.
2-Imino-4-thiazolidinones 66 were prepared by reaction of thiourea derivatives with N -(2-chloroacetyl)tetrahydroisoquinoline 65 (Scheme 31) (46).
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N
O
Cl
S
NH
NH
R2 R1+acetone, reflux N
S NR2
R1O
R1, R2 = H, alkyl, allyl, aryl65
66
Scheme 31. Synthesis of 2-Imino-4-thiazolidinones.
2.3. From cyanamide
Cyclocondensation of methyl 2-mercaptoacetate with cyanamide in methanol containing triethy-lamine afforded 2-amino-4-thiazolidinone 2 (Scheme 32) (47).
O
OMeHS + NH2NC
MeOH/Et3N N
S NH2
O
2
Scheme 32. Synthesis of 2-amino-4-thiazolidinone.
Heating thiolactic acid with cyanamide in water/ammonium hydroxide gave NH3 gas and aprecipitate of 82% 2-imino-4-oxo-5-methylthiazolidine 67 (Scheme 33) (48).
SH
CO2HMe
H2N CN
H2O/NH4OH82%
N
S
O
MeH2N
67
Scheme 33. Synthesis of 2-imino-4-oxo-5-methylthiazolidine.
2.4. From α,β-unsaturated carboxylic acids
Single-stage synthesis of 5-aroylmethyl-2-iminothiazolidin-4-ones 69 was achieved by reactionbetween β-aroylacrylic acids and thiourea. Thus, hydrochlorides, hydrobromides, and sulfates of69 were prepared in good yields by cyclocondensation of β-aroylacrylic acids 68 with thioureain the presence of the appropriate HX (Scheme 34) (49).
O
R CO2H +
S
H2N NH2
HX NH
S
O
NHR
Ox HX
R = Ph, p-MeC6H4, p-BrC6H4, p-ClC6H4, 5,6,7,8-tetrahydro-2-naphthyl; X= Br, Cl, HSO4
53–94%
68 69
Scheme 34. Synthesis of sulfates.
N -(maleoylamino)benzoic acids 70 were treated with thiourea derivatives to give thiazolidines71 (Scheme 35) (50).
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324 M.A. Metwally et al.
HN
O CO2H
R
+
S
H2N NH
R1. AcONa/Ac2O
2. dioxane
HN
S
O
NR1
O
NH
R
R = 2-, 3-, or4-CO2H; R1 = Ph, H70
71
Scheme 35. Synthesis of thiazolidines.
Reactions of thiourea with, maleic acid, fumaric acid, methyl hydrogen fumarate, or its sodiumsalt give 2-imino-2,3,4,5-tetrahydro-1,3-thiazol-5-acetic acid 72, its methyl ester 73 was preparedby heating in methanol in the presence of concentrated HCl (Scheme 36) (51).
S
HN O
OHHN
OOHO
OH
O
OHO
HO
O
OHO
O
Me
O
ONaO
O
Me
S
NH2H2N
60–85%
MeOH/HCl
78%
S
HN O
OMeHN
72
73
Scheme 36. Synthesis of methyl 1,3-thiazol-5-acetic acid ester.
Dimethyl acetylene-dicarboxylic esters (DMADCs) have been treated with thiourea to give(E)-methyl 2-(2-amino-4-oxothiazol-5(4H)-ylidene)acetate 74 (Scheme 37) (52, 53).
CO2MeMeO2Cthiourea, MeOH
91%
N
S
O
H2NOMe
O
74
Scheme 37. Synthesis of (E)-methyl 2-(2-amino-4-oxothiazol-5(4H )-ylidene)acetate.
2.5. From anhydrides or imides
Maleic anhydrides 75 reacted with thiourea to give 1,3-thiazolidine 76 (Scheme 38) (51).
O O
O
R
thiourea N
S
O
H2N CO2H
R= H, Me, Ph R75 76
Scheme 38. Synthesis of 1,3-thiazolidine.
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Reaction of 2,3-dibromosuccinic anhydride or bromomaleic anhydride 77 and thiourea gave(E)-2-(2-amino-4-oxothiazol-5(4H)-ylidene)acetic acid 78 (Scheme 39) (54).
OO
O
BrR
thiourea
41% R= Br10% R= H
N
S
O
H2NCO2H
8777
Scheme 39. Synthesis of (E)-2-(2-amino-4-oxothiazol-5(4H )-ylidene)acetic acid.
1-o-Tolyl-1H -pyrrole-2,5-dione 79 was reacted with thiourea to give 2-(2-amino-4-oxo-4,5-dihydrothiazol-5-yl)-N -o-tolylacetamide 80 in good yield (Scheme 40) (51).
N OO
Me thiourea
81%N
S
NH2O
O
NH
Me
79 80
Scheme 40. Synthesis of 2-(2-amino-4-oxo-4,5-dihydrothiazol-5-yl)-N -O-tolylacetamide.
When a buffer solution of N -ethylmaleimide and thiourea was left for 2 days at room temper-ature, N -ethyl-α-(2-imino-4-oxothiazolidin-5-yl)acetamide 81 was obtained (Scheme 41) (55).
NO O
Et
thiourea, KH2PO4
water74%
N
S
OO
NH
EtH2N
81
Scheme 41. Synthesis of N -ethyl-α-(2-imino-4-oxothiazolidin-5-yl)acetamide.
N-substituted maleimides were condensed with thiourea derivatives to give 4-thiazolidonederivatives 82 in 46–71% yields (Scheme 42) (56).
N
R
OO +
O
NH
NH
R1 R2 N
S
R2
R1O O
NH
R
R= Et, Ph; R1=R2=H, R1= H, R2= Ph, R1=R2=Ph82
Scheme 42. Synthesis of 4-thiazolidone derivatives.
2.6. From epoxides
The nucleophilic ring opening of gem-dicyano epoxides by N-substituted or N,N′-disubstitutedthioureas leads to 2-imino-4-thiazolidinones, via postulated cyanocarbonyl intermediates. Thus,reaction of 2,2-dicyano-3-phenyloxirane 83 and diphenylthiourea gave 55% diphenylthiazolidi-none 84 (Scheme 43) (57).
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O
PhNC
NC+
S
NH
NH
Ph Ph NS
OPh
NPh
Ph
55%
8384
Scheme 43. Synthesis of diphenylthiazolidinone.
Methyl E-2,3-epoxyhexadecanoate 85 reacted with thiourea to give aminotridecylthiazo-linecarboxylate 88 and tridecylmethylenethiazolinone 89 along with Z- and E-86 and 87(Scheme 44) (58).
(CH2)12Me
O
OO
Me
thiourea, DMFO
H3C (CH2)12
Me O
MeO(CH2)12
Me
30% 5%
+
N
S
O
H2N
CH
(CH2)12
MeN
SH2N
CH
(CH)12
CO2Me
32%18%
+
85
86 87
88 89
Me
Scheme 44. Synthesis of thiazolinecarboxylate and thiazolinone.
The reaction of Z-methylepoxysuccinic acid with thiourea gave 2-imino-4-oxothiazolidine 78(Scheme 45) (59).
O
HO2C CO2Hthiourea, MeOH
75%
N
S
O
H2NCO2H
78
Scheme 45. Synthesis of 2-imino-4-oxothiazolidine.
Ethylene oxide 90 and thiourea in MeOH, kept for 2 weeks at 30 ◦C, gave 2-amino-4-keto-5-isopropylidene-2-thiazoline 91 in 92% yield (Scheme 46) (60).
OMe
MeCO2Me
thiourea/MeOH
92%
N
S
O
H2N Me
Me90 91
Scheme 46. Synthesis of 2-amino-4-keto-5-isopropylidene-2-thiazoline.
Reactions of 3-chloropentafluoropropene-1,2-oxide with thiourea gave 2-amino-5-(chlorodi-fluoromethyl)-5-fluorothiazol-4(5H)-one 92 (Scheme 47) (61).
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CF2Cl
OF
F
F +
S
H2N NH2
NaHCO3, NaOH
32%
N
S
OH2N
F
CF2Cl92
Scheme 47. Synthesis of 5-fluorothiazol-4(5H )-one.
2.7. From azoalkenes
Thiourea easily reacted under very mild conditions with some conjugated azoalkenes 93 in a one-pot reaction to give 39–88% of substituted thiazolinones 94 that frequently exhibited hydrazono-hydrazino tautomerism in the chain at position 5 of the ring. The chemical structure was confirmedby x-ray diffraction (Scheme 48) (62).
O
XRNN
CH3O
MeO +S
H2N NH2
MeOHN
S
O
H2N
N
Me
NH
O
XR
69–88%
XR= NH2, NHPh, OMe93
94
Scheme 48. Synthesis of substituted thiazolinones.
2.8. From isothiourea derivatives
2-Amino-4-oxy-5-aminomethyl(ethyl)thiazolines, which have radioprotective activity, were syn-thesized. 2-Amino-4-oxo-5-aminomethyl-2-thiazoline dihydrobromide (96, n = 0) and 2-amino-4-oxo-5-aminoethyl-2-thiazoline dihydrobromide (96, n = 1) were prepared by cyclization of S-(1-carboxy-2-aminoethyl)isothiourea (95, n = 0) and S-(1-carboxy-3-aminopropyl)isothiourea(95, n = 1), respectively (Scheme 49) (63).
SCO2H
n(H2C)
NHH2N
NH2
76-80%S
n(H2C)
NH2N
NH2
O
x 2HBrx 2HBr
95 96
Scheme 49. Synthesis of 2-thiazoline.
Synthesis of 2-substituted E-5-arylidenethiazolin-4-ones 98 from α,β-unsaturated acyl isoth-iocyanates was reported. Thus, propenoylthioureas 97 were oxidized with bromine in chloroformto E-5-arylidenethiazolin-4-ones 98 (Scheme 50) (64).
R
O
NH
S
NH2
S
NH2N
O
RBr2 /CHCl3
70–76%
R = Ph, 2-furyl 8979
Scheme 50. Synthesis of E-5-arylidenethiazolin-4-ones.
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2.9. From 2-(alkylthio)-2-thiazolin-4-ones
Reactions of E-5-(arylmethylene)-2-(alkylthio)-2-thiazolin-4-ones 99 with ammonium carbonatewere reported to give 100 while reaction with aromatic primary amine and secondary aminesafforded 101 and 102 (Scheme 51) (65).
N
S
O
MeS
R
(NH4)2CO3
N
S
O
H2N
R
ArNH
R = 2-Cl, 4-Cl, 2-MeO, 3-MeO, 4-MeO;Ar = H, 4-MeC
6H4, 4-MeOC
6H
4, PhCH2, 4-MeC
6H
4CH
2, 4-MeOC
6H
4CH
2; X= CH
2, O
2N
S
O
NH
R
Ar
X
NH
N
S
O
N
R
X
99
100
101
102
Scheme 51. Synthesis of E-5-(arylmethylene)-2-thiazolin-4-ones.
2.10. Miscellaneous methods
Reaction of ethyl thiocyanoacetate with aromatic aldehydes in the presence of thioureas affordedE-5-arylidene-2-imino-4-thiazolidinones 103 (Scheme 52) (66).
O
SOEtNC
1. thiourea
2.ArCHO, EtOH
N
S
O
H2N Ar
(p-Me, o-MeO, p-NMe2)C6H4103
Scheme 52. Synthesis of E-5-arylidene-2-imino-4-thiazolidinones.
2-Iminothiazolidin-4-one 104 derivative was prepared in two steps. 1,2-Diethoxybenzene wascondensed with ethyl (chlorocarbonyl)formate followed by thiourea (Scheme 53) (67).
OEt
OEt
1. ClCOCO2Et
2. thiourea
NS O
H2N
OEt
OEt
104
Scheme 53. Synthesis of 2-iminothiazolidin-4-one.
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The reaction of ethyl-, vinyl-(trichloromethyl)carbinols 105 with aqueous thiourea wasreported. Thus, 105 and alkaline thiourea gave 27–66% of the corresponding 2-imino-4-thiazolidinones 106 (Scheme 54) (68).
R
R1OH
CCl3
thiourea
R
R1
S NH
NHO
R = Et, CH=CH2, R1 = H; R = R1 = Me106105
Scheme 54. Synthesis of 2-imino-4-thiazolidinones.
Tetrachlorobenzodioxinone 107 reacted with ethanol to give ethyl 2-benzamido-2-(2,3,4,5-tetrachlorophenoxy)acetate 108 and reacted with thiourea to give N -(2-amino-4-oxo-4,5-dihydrothiazol-5-yl)benzamide 109 (Scheme 55) (69).
O
O
O
HN Ph
O
Cl
Cl
Cl
Cl
EtOH O
O
HN Ph
O
Cl
Cl
Cl
Cl
EtO
thiourea
AcOEt
N
SH2N
O
NH
O
Ph
107 108 109
Scheme 55. Synthesis of 4,5-dihydrothiazol-5-yl)benzamide.
N -(2-amino-4-oxo-4,5-dihydrothiazol-5-yl)benzamide 110 was prepared by reaction of 4-benzyl-2-phenyloxazol-5(4H)-one with chloroanil followed by thiourea (Scheme 56) (69).
N
O
Ph
O
PhN
SH2N
O
NH
O
Ph1. o-chloroanil2. EtOH
3. thiourea
110
Scheme 56. Synthesis of N -(4,5-dihydrothiazol-5-yl)benzamide.
5-(4-Hydroxybenzyl)-2,4-dioxothiazolidine derivatives, which are useful as hypoglycemic andhypolipidemic agents, were prepared. Thus 4-(2-(4-methyl-5-phenyloxazol-2-yl)ethoxy)aniline111 was reacted with methyl acrylate and thiourea to give aminothiazolidinone 112(Scheme 57) (1).
SN
O
OO
NPh
Me
NH2
NH2
OO
NPh
Me
CH
H2C CO2Me1.
2. thiourea
111112
Scheme 57. Synthesis of aminothiazolidinone.
2-Bromo-3-[4-[2-(5-ethyl-2-pyridyl)ethoxy]phenyl]propionitrile 113 was refluxed for 6 hwith thiourea and sodium acetate in ethanol to give 59% yield of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2-imino-4-thiazolidinone 114 (Scheme 58) (70).
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CN
O
NEt
Br+
S
NH2H2NNaOAc/EtOH S
HN
O
HNO N
Et113
114
Scheme 58. Synthesis of 2-imino-4-thiazolidinone.
Vinyl 2-chloroacetate underwent nucleophilic displacement with thiourea to give 2-aminothiazol-4(5H)-one 2 (Scheme 59) (71).
CH2CH
O
O
Cl
thiourea, acetone
76%
N
S
O
NH2
2
Scheme 59. Reaction of vinyl 2-chloroacetate with thiourea.
The reaction of thiourea with oxalyl chloride permits the preparation of 2-aminothiazolidin-4-one 2 (Scheme 60) (72).
OCl
OCl
thiourea, acetone
92%
N
S NH2O
O
2
Scheme 60. Reaction of thiourea with oxalyl chloride.
The synthesis of substituted 5-(2-hydroxyethyl)-2-phenylimino-1,3-thiazolidin-4-ones 115is described, starting from phenylthioureas and 3-bromotetrahydrofuran-2-one under mildconditions (Scheme 61) (73).
OO
Br
+
S
NH
H2NAr
S
HN O
NAr OH
115
Scheme 61. Synthesis of 1,3-thiazolidin-4-ones.
3. Imino-amino tautomerism
Ramsh et al. (74) reported that 2-imino-4-thiazolinone and its 2-aryl derivatives 116 exist in thecrystal state as the amino tautomers (Scheme 62).
N
S
O
NH
R
R = H, MeO, NO2, Me2N, Br
HN
S
O
N
R
116 116'
Scheme 62. Tautomerization of 2-imino-4-thiazolinone.
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4. Reactions
4.1. Ring cleavage
2-Imino-4-thiazolidinone 2 was cleaved with aqueous sodium hydroxide. Treatment of the prod-uct with barium chloride, chloroacetic acid, or 1,2-dichloroethane gave barium 2-sulfidoacetate117, 2,2’-thiodiacetic acid 118, and 2,2’-(ethane-1,2-diylbis(sulfanediyl))diacetic acid 119,respectively (Scheme 63) (75).
S
NH
O
NHNaOH
BaCl2 OO Ba
S
95.2%
ClCH2CO2H SCO2H
CO2H
ClCH2CH2ClS S
CO2H CO2H
84%
96%
117
118
119
Scheme 63. Reactivity of 2 towards barium chloride, chloroacetic acid, and 1,2-dichloroethane.
2-Amino-5,5-dimethylthiazol-4(5H)-one 120 underwent ring cleavage when heated withaqueous sulfuric acid to give 2-mercapto-2-methylpropanoic acid 121 (Scheme 64) (76).
N
S
O
Me
Me
H2N H2SO4/H2O
34%CO2HMe
SH
Me
120 121
Scheme 64. Hydrolysis of 2-amino-5,5-dimethylthiazol-4(5H )-one.
4.2. Hydrolysis
2-Amino-5-ethylidenethiazol-4(5H)-ones underwent acid hydrolysis to give thiazolidin-2,4-dione which showed diverse biological activities (1, 11, 68, 77–88).
4.3. Acylation
Thiazolidinone 2 was acylated with methyl chloroformate to yield methyl 4,5-dihydro-4-oxothiazol-2-ylcarbamate 122 (Scheme 65) (89).
N
S NH2
O Cl OMe
O
NaOH/H2O
N
S NH
OO
OMe
1222
Scheme 65. Reaction of 2 with methyl chloroformate.
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Acetylation of 2-aminothiazolidin-4-one 76 with acetic anhydride gave N -acetyl derivative 123(Scheme 66) (90).
N
S
O
H2N CO2H
R
Ac2O N
S
O
HN
R
CO2HMe
O
R= H, Me, Ph
76 123
Scheme 66. Acetylation of 2-aminothiazolidin-4-one.
Acetyliminothiazolidinones 125 were prepared in high yields by acetylation of 124, which existin tautomeric equilibrium with 2-amino-4-hydroxythiazolines 125 (Scheme 67) (91).
N
S
OH2N
R
Ac2ON
S
OHN
R
H3CO
HN
S
O
N
R
H3C
O
R = H, Cl, Me, MeO, NO2
124 125 125'
Scheme 67. Formation of 2-amino-4-hydroxythiazolines.
Acetylation or benzoylation of pseudothiohydantoin gave 126 and 127. The reaction of 127with the corresponding aldehyde gave 128 that had tuberculostatic activity (Scheme 68) (8, 9).
S
O
NH2
Ac2O93%
S
O
NH
O
CH3
PhCOCl90%
S
O
NH
O
Ph
R1CHO
S
O
NH
O
RR1
R = Ac, R1 = Ph, p-Me2NC6H4, p-Et2NC6H4, p-[(ClCH2CH2)2N]C6H4;R = Bz, R1 = Ph, m-O2NC6H4, p-O2NC6H4, p-Me2NC6H4, p-[(ClCH2CH2)2N]C6H4, 2-furyl
2
126127
128
Scheme 68. Acylation of pseudothiohydantoin.
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4.4. Alkylation
2-Amino-5-(2-hydroxypropan-2-yl)thiazol-4(5H)-one 129 was prepared in 82% yield by alkyla-tion of 2-amino-4-thiazolidinone 2 with acetone (Scheme 69) (92).
N
S NH2
OMe2CO/Et2O
82%
N
S NH2
O
Me
Me
OH
2 129
Scheme 69. Alkylation of 2 with acetone.
Methylation of 2-aminothiazol-4(5H)-one has been reported. Treatment of 2-amino-4-thiazolidinone 2 with sodium methoxide gave 130 which underwent alkylation with methyl iodideor dimethyl sulfate to give a mixture of 131 and 132 (Scheme 70) (93).
S
NO
NH2
S
NNaO
NH
MeI or S
NO
NR
R1
S
NO
NR1
R+
MeONa
R = H, R1 = Me; R = R1 = Me
(Me)2SO4
2 130 131 132
Scheme 70. Methylation of 2-amino-4-thiazolidinone 2 .
4.5. Bromination
Bromination of 2-alkyl/arylimino-5-carbethoxythiazolidin-4-ones 49 afforded 5-bromo deriva-tives 133, which reacted with thiocarbamides to give 2-alkyl/arylimino-5-carbethoxy-5-isothiocarbamidothiazolidin-4-ones 134 and 2,7-dialkyl/arylimino-3,8-diaza-1,6-dithiaspiro[4.4]nonane-4,9-diones 135 (Scheme 71) (94).
HN
S
O
CO2Et
N
R
Br2/AcOHHN
S
O
CO2Et
N
R Br
S
NH2NH
R2 HN
S
O
CO2Et
N
R S
N
NH2
R2 HN
S
O
NR
NH
S
O
NR2+
R = H, Me, Ph, 4-MeC6H4, 4-Cl-C6H4, 2-MeO-C6H4
49 531431331
Scheme 71. Bromination of 49.
4.6. Reaction with formalin
2-Amino-5,5-bis(hydroxymethyl)-4-thiazolinone 136 was synthesized in 50% yield by treat-ing pseudothiohydantoin 2 with formalin in the presence of catalytic amount of triethylamine(Scheme 72) (95).
S
NO
OHOH
H2NN
S NH2
OHCHO/Et3N/H2O
50%
6312
Scheme 72. Formation of 2-Amino-5,5-bis(hydroxymethyl)-4-thiazolinone.
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2-[(Hydroxymethyl)amino]-4-thiazolinone 137 was prepared by reaction of 2-aminothiazol-4(5H)-one 2 with formalin (Scheme 73) (96).
N
S
O
NH2HCHO/EtOH N
SO
HN OH
2 137
Scheme 73. Formation of 2-[(Hydroxymethyl)amino]-4-thiazolinone 137.
The hydroxymethylation of 2-imino-5-arylidenethiazolidin-4-ones 138 has been reported togive (E)-5-arylidene-2-(hydroxymethylamino)thiazol-4(5H)-ones 139 (Scheme 74) (97, 98).
HN
S
OHN
R HCHO N
S
O
HN
RHO
R = H, Cl, NO2, OMe, Br, F
138 139
Scheme 74. Formation of (E)-5-arylidene-2-(hydroxymethylamino)thiazol-4(5H )-ones.
4.7. Knoevenagel condensation
5-Arylidene-2-imino-4-thiazolidinone derivatives 140 were synthesized, in 10 min with 63–91%yields, by the cross-aldol condensation of aromatic aldehydes with 2-amino-4-thiazolidinone 2in sodium acetate/acetic acid under microwave irradition (Scheme 75) (99).
N
S NH2
O
+ ArCHO ACOH/AcONa
MW, 10 min, 170°C63–91%
N
S NH2
O
Ar
2 140
Scheme 75. Formation of 5-Arylidene-2-imino-4-thiazolidinone derivatives.
5-[(3,5-Dimethoxyphenyl)methylene]-2-imino-4-thiazolidinone 141 as an anti-inflammatoryagent was synthesized from 3,5-dimethoxybenzaldehyde and 2′ via Knoevenagel condensation(Scheme 76) (6).
S
NHO
NH
OMe
MeO
NH
S NH
O
+
CHO
OMeMeO
2C' 141
Scheme 76. Formation of 5-[(3,5-dimethoxyphenyl)methylene]-2-imino-4-thiazolidinone.
5-[(4-Hydroxy)-benzylidene]thiazolidine-2,4-dione 142 (an intermediate in synthesis of antidi-abetic agents) was prepared from thiourea in four steps with overall yield of 40% (Scheme 77) (2).
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S
HN
O
O OH
S
H2N NH2
1. thiourea
2. 4-OH-C6H4CHO3. H3O+
40% 142
Scheme 77. Formation of 5-[(4-Hydroxy)-benzylidene]thiazolidine-2,4-dione 142 .
Treatment of 2-amino-4-thiazolidinone 2 with 2,5-dimethoxybenzaldehyde afforded thepotential cardiotonic Knoevenagel product 143 in 70% yield (Scheme 78) (7).
N
S NH2
O
CHO
OMe
OMe
+
N
S
O
H2N OMe
MeO143
2
Scheme 78. Formation of Knoevenagel product 143.
(5Z)-5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-aminothiazol-4(5H)-one 144 was pre-pared by Knoevenagel condensation of 2-amino-4-thiazolidinone 2 with 2,6-di-tert-butyl-4-formylphenol (Scheme 79) (100).
N
S NH2
OOHC
OH
Bu-t
Bu-t
+AcOH/AcONa
reflux, 19 h38%
N
S
NH2
O
OH
Bu-t
Bu-t
2
144
Scheme 79. Reaction of 2 with 2,6-di-tert-butyl-4-formylphenol.
Quinazolin-4(3)-ones bearing different 2-amino-4-thiazolidinone as potential antiinflammatoryagent were reported. Thus the Knoevenagel condensation of 2-amino-4-thiazolidinone 2 with3,4-dihydro-4-oxo-3-phenylquinoline-2-carbaldehyde led to (Z)-2-amino-5-((4-oxo-3-phenyl-3,4-dihydroquinolin-2-yl)methylene)thiazol-4(5H)-one 145 (Scheme 80) (101).
N CHO
O
Ph
N
S NH2
O
+EtOH/AcONa
57%
N
O
Ph
NS
NH2
O
2 145
Scheme 80. Reaction of 2 with 3,4-dihydro-4-oxo-3-phenylquinoline-2-carbaldehyde.
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Chowdhry et al. (102) reported the synthesis of bidentate ligand (Z)-2-amino-5-(pyridin-2-ylmethylene)thiazol-4(5H)-one 146 by condensation of 2-aminothiazol-4(5H)-one 2 withpicolinaldehyde (Scheme 81).
N
S NH2
ON
CHO
+1) Na2CO3, glycine
2) H2O90%
N
SNH2
O
N
2146
Scheme 81. Reaction of 2 with picolinaldehyde.
The arylidene derivatives 147 were also prepared through reaction of 2 with aromatic alde-hydes. 147 Reacted with hydrazine hydrate and urea to give thiazolodihydropyrazole 148 andthiazolotetrahydropyrimidone 149, respectively (Scheme 82) (102).
N
S NH2
O
+N
S
H2N
O
N2H4/EtOH
68%
N
SH2N
NHHNCHO
OMe
OMe
MeO
OMe
OMe
OMe
OMe
OMe
OMe
H2N NH2
O
EtOH/Na78%
HN
NH
N
S
O
NH2
OMe
OMeMeO
R = Ph, 4-ClC6H4, 3,4,5-(MeO)3C6H2
2 147148
149
Scheme 82. Formation of thiazolodihydropyrazole and thiazolotetrahydropyrimidone.
Substituted 1,5-naphthyridine thiazolinones 151 reported to have antiproliferative and anti-cancer activities. 6-Formyl-4-isopropoxy-1,5-naphthyridine-3-carbonitrile 150 was condensedwith 2-amino-4-thiazolidinone 2 to afford the Knoevenagel product 151 in 23% yield(Scheme 83) (5).
N
N
O
NC CHO N
S NH2
O
+AcONa/AcOH
23%
N
N
O
NC
N
S NH2
O
150 2 151
Scheme 83. Formation of 1,5-naphthyridine thiazolinones.
(Z)-5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methylene]-2-imino-4-thiazolidinone153 is useful as dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflammatoryactivity, and was prepared in 38% yield by reaction of 2-imino-4-thiazolidinone 2 with3,5-di-tert-butyl-4-hydroxybenzaldehyde 152 (Scheme 84) (10).
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S
HN
O
HN
OH(H3C)3C
C(CH3)3
CHO
OH
(H3C)3C C(CH3)3
+S
HN
O
HN
AcOH/AcOH
ref lux, 48 h38%
152 2 153
Scheme 84. Reaction of 2 with 3,5-di-tert-butyl-4-hydroxybenzaldehyde.
Quinolinyl-methylene-thiazolinones have been reported as potent and selective cyclin-dependent kinase 1 (CDK1) inhibitors. Thus, the Knoevenagel condensation of 2-amino-4-thiazolidinone 2 with quinoline-6-carbaldehyde derivatives 154 led (Z)-2-amino-5-((2,4-dialkylquinolin-6-yl)methylene)thiazol-4(5H)-one 155 (Scheme 85) (103, 104).
N
SNH2
O N
OHC
+AcONa/AcOH
130°C, 12h
NS
NH2
O
N
R2
R1
R1
R2
R1=R2 = H; R1 =NHAc, R2= OEt
2154
155
Scheme 85. Reaction of 2 with quinoline-6-carbaldehyde derivatives.
Quinazolinylmethylene thiazolinones as CDK1 inhibitors were prepared. Thus, the Kno-evenagel condensation of 2-amino-4-thiazolidinone 2 with 4-ethoxyquinazolin-6-carbaldehyde156 afforded stereo-selectively, (5Z)-2-amino-5-((4-ethoxyquinazolin-6-yl)methylene)thiazol-4(5H)-one 157 (Scheme 86) (105).
N
SNH2
O
N
N
OHC
OEt
+ NS
H2N
O
N
N
OEt
AcOH/AcOH
ref lux, 12h
2156
157
Scheme 86. Reaction of 2 with 4-ethoxyquinazoline-6-carbaldehyde.
Stereoselective synthesis of ethyl 3-[(9E)-(2-amino-4-oxothiazol-5(4H)-ylidene)methyl]-1H -indole-2-carboxylate 159 was achieved in 67% yield by condensation of ethyl 3-formyl-1H -indole-2-carboxylate 158 with 2-amino-4-thiazolidinone 2 under Knoevenagel conditions(Scheme 87) (106).
N
S NH2
OHN
CHO
CO2Et+
AcOH/AcONa
ref lux, 8.5 h67%
HN
CO2EtN
S NH2
O
2 158 159
Scheme 87. Reaction of ethyl 3-formyl-1H -indole-2-carboxylate.
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338 M.A. Metwally et al.
Thiazolone-based sulfonamides were prepared as inhibitors of nonstructural protein5B polymerase. Thus, 4-methylbenzene-1-sulfonyl chloride was condensed with 2-amino-4-thiazolidinone 2 to afford sulfonamide 160, that condensed with (E)-3-(pyridin-2-yl)acrylaldehyde under the Knoevenagel condition to give compound 161 (Scheme 88) (14).
N
SNH2
O
S OO
Cl
Me
+Et3N/THF
80°C, 1h
N
S
HN
O S
O
OMe
N H
HCHO
NS
HN
O
S
O
O
MeN
H
H
H
2 160
161
Scheme 88. Reaction of 2 with 4-methylbenzene-1-sulfonyl chloride.
(5E)-5-((1H -Pyrrolo[2,3-b]pyridin-3-yl)methylene)-2-aminothiazol-4(5H)-one 163 was pre-pared in 82% yield as anti-cancer agent by the Knoevenagel condensation of 2-amino-4-thiazolidinone 2 with 1H -pyrrolo[2,3-b]pyridine-3-carbaldehyde 162 (Scheme 89) (3).
N
S NH2
ON
HN
CHO
+AcONa/AcOH
reflux, 12h82%
N HN
N
SNH2
O
2 361261
Scheme 89. Reaction of 2 with 1H -pyrrolo[2,3-b]pyridine-3-carbaldehyde.
Heterocyclic arylidene aryl ether compounds are useful for treating diseases or disorders medi-ated through modulation of estrogen-related alpha receptors. The Knoevenagel condensation of 2-amino-4-thiazolidinone 2 with 4-(4-(trifluoromethyl)-2-nitrophenoxy)-3-methoxybenzaldehyde164 afforded (5Z)-5-(4-(4-(trifluoromethyl)-2-nitrophenoxy)-3-methoxybenzylidene)-2-amino-thiazol-4(5H)-one 165 (Scheme 90) (107).
N
S NH2
O
+
O
OMe
NO2
OHC CF3
EtOH/NH4OAc
ref lux, 24h98%
N
S NH2
O
O
MeO
NO2
F3C
2 164165
Scheme 90. Reaction of 2 with 4-(4-(trifluoromethyl)-2-nitrophenoxy)-3-methoxybenzaldehyde.
Thiazolinone 3,4-disubstituted quinolines as CDK1 inhibitors for treating cancer was reported.6-((15E)-(2-Amino-4-oxothiazol-5(4H)-ylidene)methyl)-4-ethoxyquinoline-3-carbonitrile 167was prepared by reaction of 2-amino-4-thiazolidinone 2 with 4-ethoxy-6-formylquinoline-3-carbonitrile 166 (Scheme 91) (4).
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N
S NH2
O
+
N
CN
OEt
OHC
AcOH/AcONa
110°C, 4h47%
NCN
OEtN
SH2N
O
2 166 167
Scheme 91. Reaction of 2 with 4-ethoxy-6-formylquinoline-3-carbonitrile.
The Knoevenagel condensation between 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde168 and pseudothiohydantoin 2 afforded (Z)-5-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzy-lidene)-2-aminothiazol-4(5H)-one 169 in 94% yield as potent and selective human β3 agonists(Scheme 92) (108, 109).
OHCO
ON
N
S NH2
O
+EtOH/piperidine
94%
NS
H2N
OCHO
ON
8612 169
Scheme 92. Reaction of 2 with 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde.
Synthesis and in vitro activity of rhodanine-based phosphodiesterase-4 (PDE4) inhibitorshas been described. Knoevenagel condensation of 2-imino-4-thiazolidinone 2 with 3-(cyclopentyloxy)-4-methoxybenzaldehyde 170 in sodium acetate/acetic acid under reflux-ing conditions for 4 h afforded 5-(3-(cyclopentyloxy)-4-methoxybenzylidene)-2-aminothiazol-4(5H)-one 171 (Scheme 93) (110).
O
OMe
OHC N
S
O
NH2
+AcOH/AcONa
reflux, 4h
NSO
NH2
O
MeO2170 171
Scheme 93. Reaction of 2 with 3-(cyclopentyloxy)-4-methoxybenzaldehyde.
Condensation of isatin derivatives 172 with 2-aminothiazol-4(5H)-one 2 in refluxing ethanolafforded isatylidene derivatives 173 in good yields, and showed promising antibacterial activity(Scheme 94) (111, 112).
NH
O
OR1
R2
+N
S NH2
OEtOH
NH
O
R1
R2
N
S
NH2
O
R1=R2=H, Me; R1= H, R2=Me
2172 173
Scheme 94. Reaction of 2 with isatin derivatives.
A facile synthesis of thiazolidinone 175 was described by the Knoevenagel-type condensation ofbenzo[b]thiophene-2,3-dione 174 (commonly known as thioisatin) with 2-amino-4-thiazolidinone2 (Scheme 95) (113).
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340 M.A. Metwally et al.
N
S NH2
OS
O
O+EtOH, reflux, 8h
72%
N
SNH2
OS
O
2 174 175
Scheme 95. Condensation of 2 with benzo[b]thiophene-2,3-dione.
The synthesis of acenaphthylidene derivative 177 involved the Knoevenagel-type condensationof 2-amino-thiazolidin-4-one 2 with acenaphthylene-1,2-dione 176 (Scheme 96) (114).
OO
N
S
O
NH2
+EtOH
reflux, 6 h87%
O
N
S
O
NH2
176177
Scheme 96. Condensation of 2 with acenaphthylene-1,2-dione.
Condensation of 2-imino-4-thiazolidinone 2 with 1,4-cyclohexanedione gave 5,5′-(1,4-cyclohexanediylidene)bis[2-imino-4-thiazolidinone] 178 (Scheme 97) (112).
HN
S
O
NH
O O
EtOH, reflux, 2 h45%
NH
S
O
NH
HN
S
O
HN
2' 178
Scheme 97. Condensation of 2 with 1,4-cyclohexanedione.
(E)-ethyl 5-amino-2-benzylidene-3-oxo-7-phenyl-3,7-dihydro-2H -thiazolo[3,2-a]pyrimi-dine-6-carboxylate 181 was obtained by reaction of (5Z)-2-amino-5-benzylidenethiazol-4(5H)-one 179 with ethyl 2-cyano-3-phenylacrylate 180 (Scheme 98) (115).
N
S
O
Ph
H2N +HC
CNEtO2C
PhEtOH/Et3N
N
N
NH2
EtO2C
Ph S
O
Ph
179 180181
Scheme 98. Formation of thiazolo[3,2-a]pyrimidine derivatives.
(E)-2-benzylidene-3,5-dioxo-7-phenyl-3,5-dihydro-2H -thiazolo[3,2-a]pyrimidine-6-carbon-itrile 183 was prepared by reaction of ethyl 2-cyano-3-oxo-3-phenylpropanoate 182 with2-amino-5-benzylidenethiazol-4(5H)-one 179 in a mixture of acetic and hydrochloric acid(Scheme 99) (116).
N
SH2N
O
Ph+ CN
CO2Et
O
Ph HCl/AcOH
60%N
N S
O
Ph
O
Ph
NC
179 182 183
Scheme 99. Reaction between 179 and ethyl 2-cyano-3-oxo-3-phenylpropanoate.
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4.8. Mannich reactions
The Mannich reaction of aminothiazolidinone 2 with aqueous formaldehyde and diphenylaminegave 44% 2-((diphenylamino)methylamino)thiazol-4(5H)-one 184 (Scheme 100) (117).
N
S NH2
OHCHO/Ph2NH
44%
N
S NH
O
NPh
Ph
2 184
Scheme 100. Formation of 2-((diphenylamino)methylamino)thiazol-4(5H)-one.
The aminomethylation of 2-iminothiazolidin-4-ones by aqueous formaldehyde and pri-mary amines was studied. Thiazolotriazines 186 were prepared in 68–91% yields by theaminomethylation of iminothiazolidinones 185 with primary amines and aqueous formaldehyde(Scheme 101) (118).
N
S
O
H2NR1
R2
RNH2/CH2O
68–91%
N
S
O
N R1
R2
N
R
R = Ph, 2-naphthyl; R1=H, R2=Et, Ph
185 186
Scheme 101. Formation of thiazolotriazines.
Similarly, iminothiazolidinone 2 gave 22 and 28% thiazolotriazines 187 with t-butylamine andbenzylamine (Scheme 102) (118).
HN
SHN
ORNH2/CH2O
22-28%
N
SN
O
CH2OHN
R
R = Me3C, PhCH2
2' 187
Scheme 102. Mannich reaction with t-butylamine and benzylamine.
Thiazolotriazinones 189 were prepared in 42–90% yields by Mannich reactions of 188 withformaldehyde and primary amines (Scheme 103) (119).
R1 = R2 = H, R3 = Me, Ph, m-, p-tolyl, p-MeOC6H4, m-ClC6H4, m-BrC6H4, m-O2NC6H4, 2-C10H7;R1 = H, R2 = Me,R3 = 2-C10H7; R1R2 = PhCH, p-ClC6H4CH, p-FC6H4CH, p-BrC6H4CH, R3 = Me; R1R2 = PhCH, R3 = Ph
HN
S
O
HN
R1
R2
R3NH2, HCHO N
S
O
N
R1
R2
NR3
188 189
Scheme 103. Formation of thiazolotriazinones.
Additionally (Z)-3-((2-iodophenylamino)methyl)-2-((2-iodophenylamino)methylaimino)thiazolidin-4-one 190 was obtained in 32% yield through the aminomethylation of 2 with2-iodoaniline (Scheme 104) (118).
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342 M.A. Metwally et al.
N
SH2N
O
CH2O
32%
NH2
I
+
NS
N
O
NH HN
I I2190
Scheme 104. Mannich reaction with 2-iodoaniline.
The aminomethylation of arylidene 2-aminothiazolidin-4-ones 138 by aqueous formaldehydeand aniline afforded thiazolotriazines 191 (Scheme 105) (118).
N
S
O
H2N
R
HCHO, PhNH2
76–90%
NS
O
NRNPh
R=Br, Cl138
191
Scheme 105. Synthesis of thiazolotriazines.
The aminomethylation of 2-imino-5-arylidenethiazolidin-4-ones 138 have been reported togive (E)-5-benzylidene-2-(piperidin-1-ylmethylamino)thiazol-4(5H)-ones 192 (Scheme 106)(96, 97).
HN
S
OHN
RHCHO, piperidine N
S
O
HNRN
R = H, Cl, NO2, OMe, Br, F
138 192
Scheme 106. Aminomethylation of 2-imino-5-arylidenethiazolidin-4-ones.
4.9. Reaction with phenylisocyanate derivatives
Thiazolidone 2 reacted with phenylisothiocyanate to give 2-imino-5-phenylaminothiocar-boxamido-4-thiazolidone 193 which was converted to a thiazolopyrazole 194, a thiazolopyridine195, and a (phenylamino)thiazoleamine 196 by reaction with hydrazine hydrate, malononitrile,and aniline (Scheme 107) (120).
N
S NH2
OPhNCS, EtOH
30%
N
S NH2
O
S
PhHN N2H4/EtOH
40%
N
S
NN
H2N NHPh
CH2(CN)2, Et3N, EtOH
60%
N S
NNH2
S
Ph
CN
H2NPhNH2 / EtOH
56%
N
SH2N
S
NHPh
NHPh
2 193194
195196
Scheme 107. Reaction of 2 with phenylisothiocyanate.
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2-Amino-4-thiazolidinone 2 was reacted with benzoyl isothiocyanate in refluxing acetoni-trile to give N -(4-oxo-4,5-dihydrothiazol-2-ylcarbamothioyl)benzamide 197 with 55% yield(Scheme 108) (121).
N
S NH2
OO
NCSPh +MeCN, reflux, 3h
55%
N
S NH
O S
NH
O
Ph
2 197
Scheme 108. Reaction of 2 with benzoyl isothiocyanate.
2-Aminothiazolidinone 198 reacted with benzoyl isocyanate and sulfurisocyanatidic chlorideto give thiazolyl ureas 199 and thioureas 200, respectively (Scheme 109) (122).
N
S
O
R1H2N
O
Ph NCO
toluene
N
S
O
R1
NH
O
NH
O
Ph
R2
R2
ClSO2
NCO
THF/H2O
N
S
O
R1
NH
R2
O
H2N
R1=H, R2 = Me; R1= H, R2= CO2Et; R1= Me, R2= CO2Et
198199200
Scheme 109. Formation of thiazolyl ureas and thioureas.
4.10. Reaction with hydrazines
The reaction of 49 with hydrazines afforded 2-arylimino-2,3,4,5-tetrahydropyrazolo[3,4-d]-thiazol-6(H)-ones 201. Bromination of 49 afforded 5-bromo derivatives 202, which upon reactionwith thiocarbamides gave 2-alkyl/arylimino-5-carbethoxy-5-isothiocarbamidothiazolidin-4-ones203 and 2,7-dialkyl/arylimino-3,8-diaza-1,6-dithiaspiro[4.4]nonane-4,9-diones 204 (Scheme 110)(38).
HN
S
O
CO2Et
NR
R1NHNH2
HN
S
R1N
NR
O
NH
Br2/AcOHHN
S
O
CO2Et
NR Br
S
NH2NH
R2 HN
S
O
CO2Et
NR S
N
NH2
R2
HN
S
O
NR
NH
S
O
NR2+
R = H, Me, Ph, 4-MeC6H4, 4-ClC6H4, 2-MeOC6H4
49201
202 203 204
Scheme 110. Reaction with hydrazines and bromine.
Pyrazolinothiazolidin-2-ones 206 were prepared from rhodamine benzylidene derivatives205 by condensation with phenylhydrazines, some of them showed antifungal activity(Scheme 111) (123).
4.11. Formation of enaminones
The enaminones of 2-aminothiazol-4(5H)-ones 207 and 208 were prepared by reac-tion of 2 with methoxy-N ,N ,N ′,N ′-tetramethylmethanediamine or t-butoxy-N ,N ,N ′,N ′-tetramethylmethanediamine in aceteonitrile. Thiooxoaplysinopsin derivative 209 was prepared
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344 M.A. Metwally et al.
N
S
O
RH2N
+ R1NHNH2
AcONa/AcOH
NH
S
N
R
O N R1
R = Ph, 4-ClC6H4, 4-MeOC6H4, 4-O2NC6H4; R1 = Ph, 4-O2NC6H4
205 206
Scheme 111. Formation of Pyrazolinothiazolidin-2-ones.
by reaction of N -substituted thiohydantoin 208, Bredereck’s reagent, and 2-methylindole(Scheme 112) (124, 125).
N
S NH2
O
NMe2
OBu-tMe2N
N
S NMe2
O
NMe2
MeCN
NMe2
OMeMe2N
MeCN
N
S N
O
Me2N
NMe2
HN
H3C
HBr/AcOH
N
S NMe2
O
NH
CH3
2
207208
209
Scheme 112. Formation of enaminones.
4.12. Different reactions
Ketoketene thioacetals, which were formed by treatment of 2-amino-1-propene-1,1,3-tricarbonitrile 210 with carbondisulphide or with phenylisothiocyanate, were allowed toreact with 2-aminothiazol-4(5H)-one 2 under phase transfer catalytic (PTC) conditions toafford thiopyrano[2,3-b]pyridine or pyrido[2,3-b]pyridine derivatives 211 and 212, respectively(Scheme 113) (126).
CN
CN
H2N
NC
N
S NH2
O
+CS2, Bu4NBrK2CO3, dioxane75%
S
N
S
CN
H2N NH2
S
H2N
PhNCS,Bu4NBrK2CO3, dioxane73%
N
N
S
CN
H2N NH2
S
H2N
Ph
2209
210211
Scheme 113. Synthesis of pyrido[2,3-b]pyridine.
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Thiazolo[3,2-a]pyrimidine 212 was prepared in one-pot reaction from 2-imino-4-thiazolidinone 2 and malononitrile (Scheme 114) (116).
N
SNH2
O
+CN
CN
EtOH/Et3N N
N
O
S
NH2
HN
2 212
Scheme 114. Reaction of 2 with malononitrile.
Dispiro[thiazolidine-2,2′-[1,3]diazetidine-4′,2"-thiazolidine]-5,5"-diacetic acid 213 was pre-pared in 60% yield by reaction of 3,4-dichlorocinnamic acid with pseudothiohydantoin 2(Scheme 115) (127).
O
CO2H
Cl
Cl
S
NH
HN
NH
S
HNO
O CO2H
CO2HO
OCl
ClCl
Cl
+N
S NH2
Otoluene
60%
2
213
Scheme 115. Formation of dispiro compound.
The reaction of 2-amino-4-oxothiazolidine-5-acetic acid 214 with p-aminostyrene in thepresence of dicyclohexylcarbodiimide (DCC) gave a new monomer 215 which was obtainedconveniently under mild conditions (Scheme 116) (77).
N
S
O
H2NCO2H
+
NH2
HCCH2
DCC N
SH2N
OO
NH
HC
CH2
214 215
Scheme 116. Reaction with p-aminostyrene.
Thiazolidineacetic acids 216 which was amidated by first making the acid chloride thenamination by morpholine, piperidine, aniline, phenylhydrazine, or prop-2-en-1-amine gave thecorresponding amides 217 and 218, respectively (Scheme 117) (128, 129).
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346 M.A. Metwally et al.
N
S
O
HO2C
N
R = H, Ph, allyl, R1 = H; R = Ph, R1 = Et, Bu, cyclohexyl, Ph;R = R1 = Me2CH, cyclohexyl; R = PhCH2, R1 = MeQ = Ph, PhNH, or CH2:CHCH2; X = CH, O
R1
R
1. SOCl2
2. QNH2
N
S
O
N
R1
R
O NHQX
NH
N
S
O
N
R1
R ON X
216
217
2181. SOCl2 2.
Scheme 117. Formation of amides.
Thiophosphorylation of thiazolidinone was achieved. Thiazolidine 220 was prepared in 25%yield by condensing 2 with o-phenyl methylphosphonochloridothioate 219 (Scheme 118) (126).
S
P MeO
ClPh +
N
SNH2
OEt3N/pyridine
25%
N
S
HN
O PS
MeOPh
219 220
Scheme 118. Synthesis of thiazolidine.
Acknowledgements
The authors would like to thank the faculty of Science & Arts in Khulais, King Abdel-Aziz University, KSA for valuablesupport.
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